Derivatives of 3-aminocarbonyl-2-oxazolidinone and their process of preparation

ABSTRACT

A COMPOUND OF THE FORMULA   2-(O=),3-(R-NH-CO-),4-(4-R2,R1,R3-PHENYL),4-R4-OXAZOLIDINE   IN WHICH R4 IS H OR PHENYL R IS PHENYL, ALKYL OR ALKENYL HAVING 1-4 C OR A CYCLOALIPHATIC HAVING 5 TO 6 C R1, R2 AND R3 IS HYDROGEN METHYL OR HALOGEN, THE COMPOUND IS FORMED BY REACTING AN ISOCYANATE   R-N=C=O   WITH AN OXAZOLIDINONE. THE COMPOUNDS POSSESS ANTICONVULSIVE MYORELAXANT, ANTIDEPRESSIVE, ANTIINFLAMMATORY, ANXIOLYLIC AND ANALGESIC PROPERTIES.

United States Patent US. Cl. 260307 C 3 Claims ABSTRACT OF THE DISCLOSURE A compound of the formula in which R, is H or phenyl R is phenyl, alkyl or alkenyl having 1-4 C or a cycloaliphatic having or 6 C R R and R is hydrogen methyl or halogen,

The compound is formed by reacting an isocyanate with an oxazolidinone.

The compounds possess anticonvulsive myorelaxant, antidepressive, antiinflammatory, anxiolylic and analgesic properties.

The present invention concerns novel derivatives of 3-aminocarbonyl-Z-oxazolidinone, their process of preparation and their therapeutic application.

The novel compounds according to the invention correspond to the general formula:

in which:

R, is either a hydrogen atom or a phenyl radical;

R represents a phenyl radical, an alkyl or alkenyl radical having 1 to 4 carbon atoms or a cycloaliphatic radical having 5 or 6 carbon atoms,

the radicals R R and R represent hydrogen a methyl radical or a halogen atom.

The process according to the invention consists in reacting an isocyanate of the formula:

A (II) in which R has the same significance as in Formula I, with an oxazolidinone of the formula:

(III) 3,754,000 Patented Aug. 21, 1973 in which R.;, R R and R have the same significance as in Formula I.

The following preparations are given by Way of nonlimitative examples to illustrate the invention.

EXAMPLE 1 3-(n-propylaminocarbonyl)-5-phenyl-2-oxazolidinone (Code No. 6913) 43 g. of 5-phenyl-2-oxazolidinone and ml. of propyl isocyanate are introduced into a reaction vessel under pressure. The mixture is heated with agitation for 1 hour at C. After cooling, the product obtained is dissolved in ml. of absolute ethanol and the mixture is boiled for 1 hour. After removal of the alcohol, an oily residue is obtained which is purified by distillation. The propylurethane layer (boiling point-=80" C. under 2 mm. Hg) is removed and the desired product is then recovered.

Boiling point: 180 C. under 0.04 mm. Hg Melting point: 30 C.

Yield: 90%

Empirical formula: C H N O Elementary analysis.Calculated (percent): C, 62.89; H, 6.50; N, 11.28. Found (percent): C, 63.07; H, 6.48; N, 11.08.

EXAMPLE H 3- (cyclohexylaminocarbonyl) -5 phe'nyl-2-oxazolidinone (Code No. 69270) 43 g. of S-phenyl-Z-oxazolidinone and 50 ml. of cyclohexyl isocyanate are introduced into a reaction vessel under pressure, and the mixture is heated for 1 hour at 150 C. After cooling, the product obtained is treated with 250 ml. of ethanol and warmed for 1 hour. After evaporation of the alcohol, the cyclohexyl urethane is removed by distillation under reduced pressure. The residue is crystallised in 95 alcohol.

Melting point: 68 C. Yield: 75% Empirical formula: C H N O Elementary analysis.-Calculated (percent): C, 66.64; H, 6.99; N, 9.72. Found (percent): C, 66.67; H, 7.13; N, 9.88.

EXAMPLE III 3-(n-propylarninocarbonyl)-5,5-diphnyl-2- oxazolidinone (Code No. 69271) 60 g. of 5,5-diphenyl-2-oxazolidinone and 60 ml. of propyl isocyanate are introduced into a reaction vessel under pressure. The mixture is heated at C. with agitation for 1 hour. After cooling, the product obtained is treated with 200 ml. of ethanol with heating. The product crystallises and is purified by recrystallisation in 96 alcohol. Y

Melting point: 89 C. Yield: 74% Empirical formula: C H N O' Elementary analysis.-Calculated (percent): C, 70.35; H, 6.22; N, 8.64. Found (percent): C, 70.15; H, 6.16; N, 8.73.

The compounds listed in the following Tables I, II

and IH have been prepared in accordance with the invention.

TABLE 1 1 H OH -R R--NH-F-N\ Elementary analysis, percent Melting Calculated Found Empirical Molecular Yield point Code number R formula weight (percent) C.) C H N C H N 68325 CeH CmHuNzO: 282.29 93 160 68.07 5.00 9.92 68.23 4.80 10.11 69255..- CHs- CuHrzNzOs 220.22 80 59.99 5.49 12.72 60.05 5.69 12.91 69261-.. CzHr- CizHuNzO: 234.25 70 74 61.52 6.02 11.96 61.36 5.99 11.93 69260 C;H7(lso) CmHmNzO: 248. 27 78 62.89 6.50 11.28 62.81 6.42 11.39 69259. CH1=CHCH2 C13H14Nz0; 246.26 62 40 63.40 5.73 11.33 63.41 5.80 11.53 69256..- C|H (n) CuHnNzO; 262.30 60 64.10 6. 92 10.68 64.22 496 10. 78

TABLE II (|}Hr- 2 RNHCN\ /0 i= a- R:=Hl

Elementary analysis, percent Melting Calculated Found Empirical Molecular Yield point Code number R formula weight (percent) C.) G H N 0 H N 6986 CuHisNrOr 358.38 89 163 73.73 5.06 7.82 73.72 5.27 8.02 CmHmNzO 310.34 116 69.66 5.85 9.03 69.61 5.81 9.29 o)- cnnmmo. 324.37 88 142 70.35 6.22 8.64 70.26 6.14 8.65 CH-CHg- CIDHISNQO' 322.35 96 70. 79 5.63 8.69 70.69 5.55 8. 78 OaoHzzNzOa 338.39 82 70.98 6.55 8.28 71.19 6.55 8.53 CaaHuNrOs 364.43 78 178 72.50 6.64 7.69 72.45 6.80 7.79

TABLE III 1 H (Mi R; R-NHCN\ /0 I G g I i= I Elementary analysis, percent Melting Calculated Found Empirical oleeular point Yield Code number R R; R, formula Weight 6 0.) (percent) 0 H N G H N 70276. CzHp H 4-CH; CuHuNzO: 248.27 70 56 62.89 6.50 11.28 62.71 6.21 11.47 C;H1(n) H 4-0113 CnHmNzO; 262.30 50 69 64.10 6.92 10.68 64.25 6.96 10.80 01 1108 H 4-CH; CuHmNaO; 262.30 60 69 64.10 6.92 10.68 64.29 6.94 10.58 02H. H 4-01 CnHnClNzO: 268. 70 80 76 53.64 4.88 10.43 53.69 4.86 10.41 CgH7(n) H 4-01 CraHwClNzO; 282.72 50 78 55.22 5.35 9.91 55.30 5.18 9.95 0 11 050) H 4-01 CmHuClNzOl 282. 75 83 55.22 5.35 0.91 55.37 5.17 10.10 CzHs 3-01 4-0] CuHuClzNaOl 303.15 112 78 47.54 3.99 9.24 47.72 3.88 9.44 0111701) 3-01 4-01 CgHflOlgNgO; 317. 72 50 49.24 4.45 8.83 49.44 4.43 8.98 C;H1(ls0) 3-Cl 4-01 CmHuClnNzO; 317.17 82 66 49. 4.45 8.83 49.21 4.49 9.02 2H5 H 4-11 CuHuFNzOl 252.24 70 86 57.14 5.20 11.11 57.80 5.24 11.16 CgHfln) H 4-F CflHwFNiO] 266.27 45 78 58.64 5.68 10.52 58. 0 5.68 10.68 03111050) H 4-F cmH FNzog 266.27 45 64 58.64 5.68 10.52 58.50 5.87 10. 71 0 H; 3-F H CnHuFNzO; 252.24 57 93 57.14 5.20 11.11 57.34 5.06 11.26 C;H1(n) 3-F H CwHwFNrO: 266. 27 45 66 58. 64 5.68 10.52 58.84 5.69 10.66 03111050) 3-! H CflEI FNgO; 266.27 50 79 58.64 6.68 10.52 58.80 5.66 10.65

The compounds of Formula I have been tested on animals in the laboratory and have shown to possess in particular anticonvulsivant, myorelaxant, antidepressive, antiinflammatory, anxiolytie and analgesic properties.

(I) Anticonvulsivant properties The compounds of Formula I possess inhibiting properties, by oral means, on the mortality provoked in the 75 mouse by the administration of convulsivant agents such as strychnine, cardiazol and nicotine. As well, they inhibit, by oral means, the tonic convulsions provoked by a supramaxinal electric shock on rats and mice.

By way of example, the results obtained with a certain number of compounds of Formula I are listed in the following Table IV:

TABLE IV Percentage protection against- Dose administered s-I e/ Electric shock Rat Mouse Code number Nico- Strych- Carditine ol (II) Myorelaxant properties Such properties are shown by an incapacity to execute reestablishment movements on a horizontally suspended metallic bar (traction test), in the rats having received, by oral means, compounds of Formula I.

By way of example, the results obtained with a certain number of compounds of Formula I are listed in the following Table V:

TABLE V Dose administered Percentage Code number (mg./kg./P) inhibition (III) Antidepressive properties The compounds of Formula I inhibit, by oral means, in rats, gastric ulcerations and ptosis and, in the mice, hypothemia and ptosis, produced by the administration of reserpine.

By way of example, the results obtained with a certain number of compounds of Formula I are listed in the following Table VI:

100 Rat-..

As a result of the values shown above and those shown in the following Table VII, the difierence between the pharmacologically active dose and the lethal dose is sufficiently great to permit the compounds of Formula I to be utilised in therapeutics.

(IV) Antiinflammatory properties Such properties are shown by a diminution of the local oedema provoked by the under-planatary injection of a phlogogenic agent such as carraghenine, in rats, followed by the oral administration of the compound of Formula I.

By way of example, the results obtained with a certain number of compounds of Formula I are listed in the following Table VII:

TABLE VII Dose administered Percentage Code number (mg./kg./PO) inhibition (V) Anxiolytic properties The compounds of Formula I possess augmentative properties, by oral means, of the number of performances of this mice subjected to a test with four plates.

The results obtained with a certain number of compounds of Formula I are listed in the following Table VIII, the dose administered being 100 mg./kg./PO.

TABLE VIII Increase in No. of performances in test with Code No. of compound tested: four plates, percent 70273 70274 70252 55 (VI) Analgesic properties The compounds of Formula I administered by oral means in mice, are capable of reducing the number of consecutive painful stretchings produced by the intraperitoneal injection of phenylbenzoquinone.

By way of example, the diminution of the painful stretchings produced by the administration of 100 mg./ kg./PO of compound Nos. 70256 and 70267 is 40% and 45% respectively.

As a result of the values shown above and those shown in the following Table IX, the difference between the pharmacologically active dose and the lethal dose is sufficiently great to permit the compounds of Formula I to be utilised in therapeutics.

The compounds of Formula I are useful in the treatment of depressions, anxiety, epilepsy and painful contractions and inflammations.

They are administered by oral means in the form of tablets, sugar-coated pills and gelules containing 50 to 400 mg. of active ingredient (1 to 6 times per day) and by rectal means in the form of suppositories containing 50 to 300 mg. of active ingredient (l or 2 times per day),

7 What we claim is: 3. A compound acording to claim 1, in which R is 1. A compound of the formula phenyl.

R, References Cited g FOREIGN PATENTS 5 277,277 12/1969 Austria. RNHCN I OTHER REFERENCES P Close, J. Am. Chem. Soc. 73, 9598 (1951).

wherein l0 R is hydrogen or phenyl, ALEX MAZEL, Primary Examiner R is phenyl or cyclohexyl, and R. V. RUSH, Assistant Examiner R R and R are hydrogen, methyl or halogen.

2. A compound according to claim 1, in which R is US. Cl. X.R.

cyclohexyl. 15 424-2 72 

